Optical isomers are often known to have enhanced biological activity over the corresponding racemates. For example, European Patent Application No. 159,864 discloses the enhanced activity of S(-)-2-(4-methoxyphenoxy)propionic acid as a taste modifier and sweetness inhibitor. Similarly, European Patent Application Nos. 2,800 and 3,890 teach the utility of R(+)-2-(4-hydroxyphenoxy)propionic acid as an intermediate for the production of R(+)-(pyridyloxyphenoxy)propionic acid derivatives which display greater herbicidal activity than the racemates. In turn, R(+)-2-(4-methoxyphenoxy)propionic acid is a desirable intermediate for the preparation of the optically active (hydroxyphenoxy)propionic acid.
Various methods for obtaining high concentrations of optical isomers are known. In addition to the resolution of a racemic mixture into its optically active components which, for example, depends on the conversion to diastereomers and subsequent physical separation, individual enantiomers can be obtained by direct synthesis employing an appropriate optically active starting material. For example, optically active 2-substituted propionic acids are conveniently prepared by the reaction of either an optically active 2-halopropionic acid or an optically active alkyl or aryl sulfonate of lactic acid with an appropriate nucleophile. Such nucleophilic displacement reactions generally occur with inversion of configuration of the asymmetric carbon atom of the starting material Therefore, to prepare the R-enantiomer of the 2-substituted propionic acid, the S-enantiomer of the 2-halopropionic acid or sulfonate ester of lactic acid is employed as the starting material.
Theoretically, one can obtain essentially 100 percent of the desired enantiomer by this method. In practice, however, the optical purity of the final product is largely determined by (a) the optical purity of the starting material, (b) the nature of the leaving group and (c) the specific conditions employed. Typically, one obtains products containing a ratio of from 70 to 90 percent of the desired enantiomer and, correspondingly, 10 to 30 percent of the other optical isomer. Such products are then said to possess an optical purity of 40 to 80 percent, i.e., from 40 to 80 percent of the mixture is the desired enantiomer and from 20 to 60 percent is a racemic mixture.
The importance of the nature of the leaving group in the starting propionic acid is illustrated in the article of G. Sakata et al. in J. Pesticide Sci., 10, 69-73 (1985). Products of the following optical purities were obtained with different leaving groups under comparable conditions: tosylate (.about.80 percent): mesylate (.about.45 percent): bromide (.about.45 percent): and chloride (.about.10 percent). Thus, although optically active 2-chloropropionic acid derivatives may be the most preferable starting material from the viewpoint of cost and availability, they are the least advantageous with respect to optical purity of the product.
Similarly, the importance of the reaction conditions is well known. For example, as shown in U.S. Pat. No. 4,532,328, the optical purity of the final product can be substantially enhanced by employing a 5 to 20 fold molar excess of the optically active starting material. Although enhanced optical yields are achieved, large amounts of relatively expensive optically active reagents such as S-methyl 2-chloropropionate must be recovered and recycled. Furthermore, this reagent may be susceptible to racemization under the reaction and recovery conditions thus precluding its direct recycle in the process.